Substituted urea-amide complex



United States Patent SUBSTITUTED UREA-AMIDE COMPLEX Robert C. ONeill,New York, N. Y., and Arthur J. Basso, Colonia, N. J., assignors to Merck& Co., Inc., Rahway, N. J., a corporation of New Jersey No Drawing.Application February 11, 1955, Serial No. 487,721

18 Claims; (Cl. 167-531) ll NHCNH X RI R! N \R wherein R is hydrogen ora lower alkyl group, R is an electron withdrawing group, R is hydrogenor an alkyl or aryl radical containing less than eight carbon atoms andX is oxygen or sulfur.

These amide'substituted urea complexes are new chemical compounds. Theyare equimolar complexes which have their own characteristic propertiesthat are markedly different from the component parts and are not meremixtures of a substituted urea and an amide or thioamide.

These novel amide-substituted urea complexes are produced by reacting asubstituted urea compound rep resented by the formula- X NHHlNH R r Rwherein R is hydrogen or a lower alkyl group and R is an electronwithdrawing group and X is oxygen or sulfur, with an amide compoundrepresented by the formulawherein R and X are as defined above and R" ishydrogen, or, an alkyl or aryl radical containing less than eight carbonatoms.

In discussing the present invention, for purposes of convenience, theterm amide has been used as inclusive of thioamides, substituted amidesand thioamides.

The substituted urea compounds which may be employed as one of thestarting materials in this process are carbonilide compounds having anelectron withdrawing group in either or both of the 4 and 4-positions ofthe rings. Examples of electron withdrawing groups which may be used arenitro, cyano, carboxy, carboalkoxy, acetyl,

ice

trimethyl ammonium, sulfonic acid and carbamide groups. Such groups arealternatively referred to as meta directing (see Fieser & Fieser,Organic Chemistry, 2d edition, 1950, page 595). Specific carbanilidecompounds which may be employed include 4,4-dinitrocarbanilide; 2 methyl4,4 dinitrocarbanilide; 4 nitro 4 cyanocarbanilide; and4-nitro-4-acetocarbanilide.

The amide compounds which may be employed in this invention includeformamide, dimethylformamide, dimethylacetamide, dimethylthioacetamide,dimethylbenzamide and the like.

In accordance with one procedure for carrying out the process of thisinvention, the solid substituted urea com pound is reacted with asolution of the amide compound. The reaction mixture in which thesubstituted urea compound is ordinarily insoluble or very slightlysoluble is stirred until the insoluble complex is formed. The insolubleamide-substituted urea complex may then be filtered, washed and dried.

In those cases Where the amide compound is a liquid under reactionconditions an excess of the amide itself may be used as the solvent.

The reaction solvent is not critical. Ethers such as dioxane and ethylether, alcohols such as the lower aliphatic alcohols, hydrocarbons suchas benzene, toluene, water and mixtures of such solvents may be employedsatisfactorily. It has been found advantageous to employ a solvent inwhich the amide is soluble and in which the substituted urea isinsoluble.

Alternately, para-nitrophenylisocyanate may be treated with water in thepresence of the amide. The 4,4'-dinitrocarbanilide thus formed reactswith the amide to form the amide-4,4'-dinitrocarbanilide complex.

As the substituted urea compound it is preferred to employ4,4'-dinitrocarbanilide, although, other carbanilides having differentelectron withdrawing groups in the 4 and 4-positions may be used.Typical substituents which may be present in these positions are nitro,cyano, carboxy and carboalkoxyl radicals. Furthermore, the electronwithdrawing groups of the 4 and 4-positions need not be the same. Thustypical examples of 4,4-disubstituted carbanilides useful in thisinvention are 4,4-dinitrocarbanilide; 4,4'-dicyanoearbanilide; and4-nitro-4-cyanocarbanilide.

The amide'substituted urea complexes prepared in accordance with thisinvention are active against the widespread poultry disease commonlycalled Coccidiosis which is caused by species of protozoan parasites ofthe genus Eimeria. In this regard, E. tenellu is responsible for asevere and frequently fatal infection of the cecum of chickens.Furthermore, other serious infections are caused in fowl by otherspecies of Eimeria and especially E. acervulina, E. necatrix, E. maxima,and E. brunetti. If left untreated, such infections often causeextensive losses of fowl. The elimination or control of coccidiosis is,therefore, of the utmost importance for successful poultry raising.

According to a further embodiment of this invention, novel compositionsuseful in the treatment of coccidiosis are provided containing anamide-substituted urea complex as an active ingredient. Thesecompositions comprise an amide-substituted urea complex intimatelycombined with an inert carrier. In this regard compositions whichcontain a compound of the formula- X NHiiNH wherein R is hydrogen orlower alkyl groups, R is an electroii withdrawing group, R is hydrogenor an alkyl or aryl radical containing less than eight carbon atoms, andX is oxygen or sulfur, as 'the active ingredient has been found to beparticularlyuseful against coccidiosis.

These compositions comprise at least one of the amide-substituted ureacomplexes mentioned above combined with an inert carrier or diluent.Such compositions are conveniently produced by intimately dispersing theactive ingredient throughout a carrier. The carrier or diluent may beeither liquid or solid. Liquid dispersions can be preparedsatisfactorily by using emulsifiers and surface active agents, Any solidcan be used as a carrier which is inert toward the active compounds andwhich can be administered to animals with safety. Examples ofsuitablecarriers are ground oyster shells, attapulgus clay and ediblevegetable materials such as commercial animal, and poultry feeds, urea,corn meal, ground corn, citrus meal, fermentation residues anddistillers dried grains. The active ingredient is convenientlydispersed, in a solid carrier by conventional methods such as stirring,tumbling, and grinding. In this manner, by selecting different carriersand by altering the ratio of carrier to active ingredient, compositionsof varying concentration can be prepared. Compositions very suitable foraddition to poultry feed, may contain from about to about 40% of the newcoccidiostat, and preferably about -25%, adsorbed on or mixed with acarrier.

Premixes of 4,4 dinitrocarbanilide-dimethylformamide complex may beprepared as referred to above in a general manner. Two satisfactoryformulations are described in detail below.

A. Ingredients:

a. 4,4 dinitrocarbanilide-dimethylformamide complex b. Corn distillersdried grains 0. Wheat shorts d. Dried vitamin B12 fermentation solublesC0mpositi0n.-Each pound of the mixture preparation contains 0.30 poundof coccidiostat drug. In order to prepare 1000 pounds of feed premix thefollowing quantities are employed:

a, 300 pounds 4,4-dinitrocarbanilide-dimethylformamide complex b. 175pounds corn distillers, dried grains (through 30 mesh screen) i c. 455pounds wheat shorts (30-80 mesh) d. 70 pounds dried vitamin B12fermentation solubles (30-8 0 mesh) i The total amounts of wheat shortsand fermentation solids, and about 150 pounds of corn grains are mixedfollowed by the drug and the remainder of the corn grains.

- 4 After mixing for about two hours the material is ready forpackaging.

B. Ingredients:

a. 4,4 dinitrocarbanilide-dimethylformamide b. Corn distillers driedgrains c. Wheat shorts (1. Dried vitamin B12 fermentation solublesC0mp0sition.-Each pound of the mixture contains 0.25 pound ofcoccidiostat.

Preparation-The following quantities are employed in order to make 995pounds of product:

a. 250 pounds 4,4-dinitrocarbanilide-dimethylformamide b. 188 poundscorn distillers dried grains (through 30 mesh screen) c. 487 poundswheat shorts (3080 mesh) 7 a. 70 pounds dried vitamin B12 fermentationsolubles (30-80 mesh) I Products such as the above are suitable forincorporation into poultry feedstufls in order to obtain the desireddosage level of active drug.

The amount of active ingredient required for effective prophylacticcontrol of coccidiosis is very low. With regard to poultry, good resultshave been obtained by the administration. of a quantity of the activeingredient equal to about .005% tov .05% of the food consumed. Optimumresults are usually obtained by the daily administration of a quantityof active ingredient equal to about .0075% to about .025% of the foodconsumed. Such relatively small amounts may be conveniently incorporatedin the normalv ration prior to feeding the poultry. Largerconcentrations of up to about 0.1% of the active ingredient may beemployed therapeutically if an utbreak of the disease is encountered.

The coccidiostatic activity of compositions containing variousamide-substituted urea complexes was experimentally demonstratedaccording to the following test:

Groups of 10 two-week old chicks were fed a mash feed containing from0.01% to 0.04% of the active ingredient uniformally dispersed therein.After existing on the diet for 24 hours, each chick was inoculated with50,000 sporulated oocysts of E. tenella. In addition, groups of 10chicks were also infected but fed a diet free of the active ingredientand used as positive controls. Still other groups were treatedseparately with the substituted urea compound and the amide compound andwith physical mixtures of the substituted urea compound and the amidecompound. The experiment was terminated after administering therespective diets for seven days after inoculation and. the followingresults were obtained. The oocyst count (number of parasites of E.tenella remaining) was determined by sacrificing the birds and examiningthe infected organs microscopically.

TABLE I.ANTICOCCIDIAL TESTING RESULTS 000 st Count Percent Wei htPercent Percent Mortality g am 5 Compound gfi In Diet Un- Un- Un-Treated treated Treated treated Treated heated 0.1 0 40 34 60 454,4-d1n1trocarbanl11do 0. 05 0 40 28 34 66 45 v H 0.025 40 29 34 54 454,4-dinitroearbumhde-formamide 0. 1 0 30 0. 2 81 25 complex 0. 05 0 1. 025 72 25 4,4-dinitroearbamhde-dimethyl 0.1 0 40 0.4 18 66 iormamidecomplex 0.05 0 30 1. 6 18 73 44 0.1 0 5 0.1 28 46 314,4-dm1troearbaml1de-dimethyl- 0. 05 0 5 1 28 47 31 aoetamide complex 0.06 0 33 1 23 32 21 0. 1 0 47 O 1 20 24 0 It will be noted from Table 1that 4,4-dinitrocarbanilide when administered separately, does haveactivity, but such activity does not approach that displayed by thecomplex. The complexing agents of themselves are inactive.

The following examples are intended to be illustrative only and may bevaried or modified without departing from the spirit and scope of thisinvention.

Example 1 4,4J-DINITROCABBANILIDE-FORMAMIDE COMPLEX Nine grams of 4,4'dinitrocarhanilide was stirred with 50 ml. of formamide at steam bathtemperature for four hours. The resulting4,4'-dinitrocarbanilide-formamide complex was filtered, washed withethyl alcohol and ethyl ether and air dried. This product had a meltingpoint of 262 C. (sealed tube) and weighed 9.78 grams.

A solution 01515.3 grams of para-nitrophenylisocyanate in 70 ml. ofmoist dioxane was added to 248 ml. of dimethylformamide at roomtemperature. 1 The resulting suspension was allowed to stand at roomtemperature with stirring for two hours. i The insoluble4,4-dinitrocarbanilide-dimethylformamide complex thus formed wasfiltered and air dried to constant weight. The product weighed 10.7grams.

Example 3 4,4-DINIT R OTHIOCARBANILIDE'DIMETHYLFORM- AMIDE COMPLEX 6Example 4 Twenty grams of 4,4-dinitrocarbanilide was added to 100 ml. ofdimethylacetamide. The mixture was stirred for one and one-half hours,during which time the solid 4,4'-dinitrocarbanilide-dimethylacetamidecomplex precipitated. The reaction mixture was filtered, the precipitatewashed with ether and air dried to yield 24.5 grams (95.4% of4,4-dinitrocarbanilide dimethylacetamide complex having a melting pointof 270-275 C. (with decomposition in a sealed tube).

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of this invention. 1

What is claimed is:

l. A compound of the formula R wherein R is selected from the groupconsisting of hydrogen and lower alkyl groups, R is an electronwithdrawing group, R" is selected from the group consisting of hydrogenand alkyl and aryl radicals containing less than eight carbon atoms andX is selected from the group consisting of oxygen and sulfur.

2. A compound of the formula-- wherein R is selected from the groupconsisting of hydro gen and lower alkyl groups and R is an. electronwithdrawing group, at least one R being a nitro group, R

is selected from the group consisting of hydrogen and alkyl and arylradicals containing less than eight carbon atoms and X is selected fromthe group consisting of CH; oxygen and sulfur. s 3. A compound of theformula- NHiiNn O X 4 H-C CH; NH NH\ X \N n 0 R OzN N02 i l 0-N NOr NThree grams of 4,4'-dinitrothiocarbanilide was added to 45 ml. ofdimethylformamide at room temperature with stirring. At the end ofninety minutes the insoluble 4,4-dinitrothiocarbanilidedimethylforrnamide complex was isolated by filtration, washed with etherand air dried.

wherein R is selected from the group consisting of hydrogen and loweralkyl groups, R is selected from the group consisting of hydrogen andalkyl and aryl radicals containing less than eight carbon atoms and X isselected from the group consisting of oxygen and sulfur.

4. 4,4-dinitrocarbanilide-dimethylformamide complex.

5. 4,4-dinitrocarbanilide-formamide complex.

6. 4,4-dinitrocarbani1ide-dimethylacetamide complex.

7. The process which comprises reacting a compound represented by theformulawherein R is as above and R is selected from the group 7consisting of hydrogen and alkyl and aryl radicals containing less thaneight carbon atoms to form a complex represented by the formulawhereinR, R, R" and X are as above.

8. The process which comprises reacting a compound represented by theformula- NHENH MG @211;

wherein R is selected from the group consisting of hydrogen and loweralkyl groups and R is an electron withdrawing group at least one R beinga nitro group and X is selected from the group consisting of oxygen andsulfur with a compound represented by the formula-- wherein R is asabove and R is selected from the group consisting of hydrogen and alkyland aryl radicals containing less than eight carbon atoms to form acomplex represented by the formula wherein R, R, R and X are as above.

9. The process which comprises reacting a compound represented by theformulawherein R iscse lected from the group consisting of hydrogen andlower alkyl groups and X is selected from the group. consisting ofoxygen and sulfur with a compound represented by the formula--- Vwherein R is as above and R is selected from the group consisting ofhydrogen and alkyl and aryl radicals containing less than eight carbonatoms to form a complex represented by the formulawherein R, R and X areas above.

10. The process which comprises reacting 4,4-dinitrocarbanilide withformamide to form 4,4-dinitrocarbanilide-formamide complex.

11. The process which comprises reacting 4,4-dinitrocarbanilide withdimethylformamide to form 4,4-dinitrocarbanilide dimethylformamidecomplex.

12. The process which comprises reacting 4,4-dinitrocarbanilide withdimethylacetamide complex to form 4,4- dinitrocarbanilidedimethylacetamide complex.

13. A composition useful against coccidiosis which comprises an inertcarrier and a compound represented by the formula wherein R is selectedfrom the group consisting of hydrogen and lower alkyl groups, R is anelectron withdrawing group, R is selected from the group consisting ofhydrogen and alkyl and aryl radicals containing less than eight carbonatoms and X is selected from the group consisting of oxygen and sulfur.e

14. A composition useful against coccidiosis which comprises an animalfeedstufl'} and a compound represented by the formulae wherein R isselected from the group consisting of hydrogen and lower alkyl groups, Ris an electron withdrawing group, at least one R being a nitro group, Ris selected from the group consisting of hydrogen and alkyl and arylradicals containing less than eight carbon atoms and X is selected fromthe group consisting of oxygen and sulfur.

15. A composition useful against coccidiosis which comprises4,4-dinitrocarbanilide-formamide complex intimately dispersed in aninert carrier.

16. A composition useful against coccidiosis which comprises 4,4dinitrocarbanilide dimethylformamide complex intimately dispersed in'aninert carrier.

17. A composition useful against coccidiosis which comprises 4,4dinitrocarbanilide dimethylacetamide complex intimately dispersed in an'inert carrier.

18! The process which comprises reacting para-nitrophenyl isocyanatewith water in the presence of a compound represented by the formularadicals containing less than eight carbon atoms to form a complexrepresented by the formula 10 wherein R, R" and X are as above.

No references cited.

13. A COMPOSITION USEFUL AGAINST COCCIDIOSIS WHICH COMPRISES AN INERTCARRIER AND A COMPOUND REPRESENTED BY THE FORMULA-